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Overexpression of the Growth arrest specific 1 (Gas1) gene reduces the in vivo progression of murine hepatocellular carcinoma and restores gene expression level

ABSTRACT: Mice developing diethylnitrosamine (DEN)-induced hepatocellular carcinoma were transfected in vivo with Gas1 by hydrodynamic gene delivery. The treatment significantly (p < 0.05) reduced the number of large tumors (more than 2 mm diameter) and histological analyses revealed that the number of carcinoma foci in liver was reduced in favor of less malignant lesions, such as hyperplastic areas, and that the number of lung metastases was also diminished. To study the effects of DEN and the subsequent transfection with Gas1, an expression microarray experiment was designed in which the transcription of 20758 genes in liver was determined. A triangular analysis of microarray data shows that transfection with Gas1 restores the level of transcription level of 182 out of the 698 genes, whose expression was affected by DEN. Therefore, transfection of liver tumor-bearing animals with Gas1 significantly reduces the size and proliferative activity of tumors and restores the transcriptional profile of the liver.

ORGANISM(S): Mus musculus

PROVIDER: GSE63574 | GEO | 2015/07/31

SECONDARY ACCESSION(S): PRJNA268293

REPOSITORIES: GEO

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Overexpression of the Growth arrest specific 1 (Gas1) gene reduces the in vivo progression of murine hepatocellular carcinoma and restores gene expression level

Project description:Mice developing diethylnitrosamine (DEN)-induced hepatocellular carcinoma were transfected in vivo with Gas1 by hydrodynamic gene delivery. The treatment significantly (p < 0.05) reduced the number of large tumors (more than 2 mm diameter) and histological analyses revealed that the number of carcinoma foci in liver was reduced in favor of less malignant lesions, such as hyperplastic areas, and that the number of lung metastases was also diminished. To study the effects of DEN and the subsequent transfection with Gas1, an expression microarray experiment was designed in which the transcription of 20758 genes in liver was determined. A triangular analysis of microarray data shows that transfection with Gas1 restores the level of transcription level of 182 out of the 698 genes, whose expression was affected by DEN. Therefore, transfection of liver tumor-bearing animals with Gas1 significantly reduces the size and proliferative activity of tumors and restores the transcriptional profile of the liver. Here we studied effects of diethylnitrosamine treatment of mice on the transcription of 20758 liver genes and the consequences of transfecting the livers with Gas1.

2015-07-31 | E-GEOD-63574 | biostudies-arrayexpress

GAS1 is required for Notch-dependent facilitation of SHH signalling in forebrain development

Project description:A Gas1 knockout was made by replacing the Gas1 coding region with a LacZ gene. The ventral neuroepithelial midline of the rostral diencephalon of Gas1 wild type and mutant embryos at E10 were isolated using laser capture microdissection. In total five replicates for wild type and four replicates for Gas1 mutant embryos were analyzed. Each replicate consisted of a pool of five embryos of the respective genotype.

2021-10-26 | E-MTAB-10207 | biostudies-arrayexpress

A novel lncRNA GAS1 promotes gastric carcinogenesis and acts as a modular scaffold of WDR5 and KAT2A complexes to specify the histone modification pattern [RNA-seq]

Project description:To elucidate whether GAS1 plays a role in gastric cancer tumorigenesis, a RNA-seq analysis was performed to compare the gene expression profiles of GAS1 shRNA and control shRNA transfectants.

2016-10-04 | GSE63764 | GEO

Single-cell RNAseq analysis of Gas1-creER-marked bone marrow stromal cells in young bones [Gas1CE;R26RtdT]

Project description:A single cell transcriptomic profile of Gas1-creER-marked bone marrow stromal cells of the murine femur at postnatal day 23 (P23), pulsed at P21.

2021-10-16 | GSE185790 | GEO

Influence of G0s2 gene knockdown on primary hepatocyte

Project description:Hepatocellular carcinoma is the third leading cause of cancer death worldwide, and it is necessary to elucidate the mechanism of hepatocarcinogenesis. Circadian clock systems have been related in cell cycle and carcinogenesis. In this study, hepatocarcinogenesis induced by DEN administration in mice was inhibited by knockdown of G0s2 at early stage in carcinogenesis. In addition, the circadian expression of G0s2 in mouse liver was regulated by RARM-NM-1 controlled by clock genes and ATRA. Moreover, mice administered both ATRA and DEN were not induced hepatocellular carcinoma, and decreased the expression of G0s2 at second day after the initiation of administration. These findings suggest that the control of G0s2 expression is important in carcinogenesis and G0s2 might be the novel target for prevention, diagnosis and treatment of hepatocellular carcinoma. Differential gene expression between G0s2 siRNA or Control siRNA transfected primary hepatocyte was measured after 24 hr of transfection.

2013-08-01 | E-GEOD-39288 | biostudies-arrayexpress

Quantitative Proteomics of Mouse Liver (FTO-KO,WT) in response to DEN injection

Project description:Single nucleotide polymorphisms in the FTO gene encoding a m6A demthylase are associated with obesity and cancer development. However, the functional role of FTO in the developemnt of progression of hepatocellular carcinoma (HCC) as a proteotypic obesity-associated cancer remains unclear. Here, we have generated mice with hepatic FTO deficiency (FTOL-KO) and subjected them to DEN induced HCC-development. FTOL-KO mice exhibit increased HCC burden. While control mice exhibit a dynamic regulation of FTO upon induction of liver damage, this response is abrogated in mice lacking FTO. Proteomic analyses revealed that liver damage-induced increases in FTO expression promotes m6A-demethylation of CUL4A reducing its protein expression. Functionally, knockdown of CUL4A restores the increased hepatocyte proliferation observed upon loss of FTO. Collectively, our study reveals a protective role for FTO-dependent dynamic m6A mRNA demethylation of CUL4A in the initiation of HCC development.

2020-11-03 | PXD018223 | Pride

TCF7L1 regulates colorectal cancer cell migration and invasion by repressing GAS1 expression (ChIP-Seq)

Project description:Dysregulation of the canonical Wnt/β-catenin signaling pathway is a hallmark of colorectal cancer (CRC). The T-cell factor/lymphoid enhancer factor (TCF/LEF; hereafter, TCF) family of transcription factors are critical regulators of canonical Wnt/β-catenin target gene expression. Despite similarity across DNA-binding and protein-binding domains, TCF family members differentially regulate target gene expression in CRC. Of the four TCF family members, TCF7L1 predominantly functions as a transcriptional repressor and it has an oncogenic role in CRC. Despite this role, few target genes regulated by TCF7L1 in CRC have been identified. Through RNA-sequencing of transcripts differentially expressed in control and TCF7L1-overexpressing HCT116 cells, we identified 397 genes that were repressed directly, or indirectly, by TCF7L1. Gene set enrichment analysis found genes associated with epithelial-mesenchymal transition amongst those that are differentially expressed. By silencing and overexpressing TCF7L1 in CRC cell lines, we found that TCF7L1 promoted migration, invasion, and adhesion in vitro. Chromatin immunoprecipitation followed by sequencing (ChIP-sequencing) localized 3661 TCF7L1 binding sites within the CRC genome. Comparison of genes whose expression was downregulated by TCF7L1 and genes with TCF7L1 binding sites revealed 41 novel targets directly regulated by TCF7L1. Among these, we localized a TCF7L1 promoter-proximal binding site within the growth arrest specific 1 (GAS1) gene. We found that ectopic GAS1 expression rescued the TCF7L1-mediated increase in migration and invasion in CRC cells. These findings uncover a novel role for TCF7L1 in repressing GAS1 expression to promote migration and invasion of CRC cells in vitro.

2024-06-05 | GSE241026 | GEO

TCF7L1 regulates colorectal cancer cell migration and invasion by repressing GAS1 expression (RNA-Seq)

2024-06-05 | GSE241025 | GEO

Gene-expression profiles of liver and hepatocellular carcinoma induced by diethylnitrosamine (DEN) in KLF6 +/- and wild type KLF6 mice.

Project description:Gene-expression profiles of liver and hepatocellular carcinoma induced by diethylnitrosamine (DEN) in KLF6 +/- and wild type KLF6 mice. Inactivation of the KLF6 tumor suppressor is common in HCC due to hepatitis C virus (HCV), consistent with its anti-proliferative activity in HCC-derived cell lines and in hepatocytes of transgenic mice. We have evaluated the impact of KLF6 depletion on human HCC and experimental hepatocarcinogenesis. In patients with surgically resected HCC, those with significantly reduced tumor expression of KLF6 had a significantly decreased survival. We modeled this event in KLF6 +/- mice, which displayed significantly more tumorigenicity than KLF6 +/+ animals in response to the hepatic carcinogen DEN, associated with recapitulation of gene signatures in both surrounding tissue and tumors that are associated with aggressive human HCCs. In DNA microarrays, mdm2 mRNA expression was increased in tumors from KLF6 +/- compared to KLF6 +/+ mice, which was validated by realtime qPCR and Western blot in both human HCC and DEN-induced murine tumors. Moreover, chromosomal immunoprecipitation and co-transfection assays established the P2 intronic promoter of mdm2 as a bona fide transcriptional target repressed by KLF6. Whereas KLF6 over-expression in HCC cell lines led to reduced MDM2 levels and increased p53 protein and transcriptional activity, reduction in KLF6 by siRNA led to increased MDM2 and reduced p53. Our findings indicate that KLF6 deficiency contributes significantly to the carcinogenic milieu in human and murine HCC, and uncover a novel tumor suppressor activity of KLF6 in HCC, by linking its transcriptional repression of MDM2 to stabilization of p53. Keywords: Liver, Hepatocellular carcinoma, Expression array, Exon array, Affymetrix

2011-08-01 | GSE23375 | GEO

Influence of DEN in mice liver

Project description:Hepatocellular carcinoma is the third leading cause of cancer death worldwide, and it is necessary to elucidate the mechanism of hepatocarcinogenesis. Hepatocellular carcinoma (HCC) has a high mortality rate and develops based on the chronic inflammatory hepatic disease. Therefore, novel prophylactic or therapeutic strategies are required to improve outcome. In this study, influence of diethylnitrosamine (DEN) and retinoic acid (ATRA) on hepatocarcinogenesis was investigated in mouse. These results suggest that the control of NF-M-NM-:B signaling during the early stage of HCC development is important for the prevention of malignant transformation in hepatocytes. Genes induced by the following treatments in mice liver were investigated at 2 days or 7 days after treatment; DEN: diethylnitrosamine (treatment of DEN (drinking water 80 mg/L)) ATRA: retinoic acid (treatment of ATRA (drinking water 30 mg/L)) G0s2 siRNA : G0s2 knockdown mouse liver (treatment of G0s2 siRNA) Control siRNA: treatment of scramble siRNA (negative control)

2014-06-06 | E-GEOD-57798 | biostudies-arrayexpress

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